Terminalia chebula Retz. (Combretaceae) (“TC”) has been extensively used in Ayurveda, Unani and Homoeopathic systems of medicines for improvement of different health conditions, e.g., constipation, diarrhoea, ulcers, gastroenteritis, asthma, cough, dyspnea, dyspepsia, hemorrhoids, candidiasis, parasites, malabsorption syndrome, hepatomegaly, vesicular and renal calculi, urinary discharges, tumors, skin diseases, leprosy, intermittent fever, rheumatism, arthritis, gout, neuropathy, paralysis, memory loss, epilepsy, depression, leucorrhea, diabetes, cardiovascular diseases, anorexia, and wounds, among others (See, B. Das, Materia Medica of Ayurveda (New Delhi: B. Jain Publishers, 1991), p. 8; K. R. Kirtikar and B. D. Basu, “Terminalia chebula.” In: Indian Medicinal Plants, (2nd Edn., Allahabad, India: Lolit Mohan Basu Publication, 1935), pp. 1020-23; and P. V. Sharma, Dravya Guna Vigyana (Vol. 2, Varanasi: Chaukhamba Bharati Academy, 1995), pp. 753-58). T. chebula fruit and its different solvent extractives were reported to exhibit hepatoprotective, cardioprotective, antimutagenic/anticarcinogenic, cytoprotective, radioprotective, antioxidant and adaptogenic, antimicrobial, antifungal, antiviral, antiamoebic, immunomodulatory, antidiabetic, wound healing, antispasmodic, and purgative activities in various animal models (S. S. Tasduq, et al., Human and Exp. Toxicol. (2006) 25: 11-18; H. Y. Cheng, et al., Biol. Pharm.Bull. (2003) 26:1331-5; S. Kaur, et al., Mutagen Res. (1998) 419: 169-79; Suthienkul, et al., South-East Asian Journal Trop. Med., Public Health (1993) 24: 751-5; Ahmad, et al., J. Ethnopharmacol. (1998) 62: 183-93; and N. K. Rao, et al., BMC Complement Altern. Med. (2006) 6: 127-32).
Terminalia chebula (T. chebula) is rich in tannoid principles. The chief constituent tannoids in the fruit are chebulinic acid, chebulagic acid, corilagin and a tannoid metabolite, gallic acid (J. Bruneton. Pharmacognosy, Phytochemistry, Medicinal Plants. (Paris, France: Laviosier Publishing, 1995), p. 333). Other minor hydrolyzable tannoids reported in T. chebula include punicalagin, chebulanin, neochebulinic acid, 1,2,3,4,6-penta-O-galloyl-β-D-glucose, 1,6,-di-O-galloyl-D-glucose, casuarinin, 3,4,6-tri-O-galloyl-D-glucose, and terchebulin (L. J. Juang, et al., J. Sep. Sci. (2004) 27: 718-24). One source lists T. chebula as having a tannoids content of about 32% by weight (W. Evans. Trease and Evan's Pharmacology. (14th Ed., W. B. Saunders Co. Pvt. Ltd., 1996), p. 493). Other constituents reported in T. chebula include fructose, amino acids, succinic acid, beta-sitosterol, resin and purgative principles of anthroquinone, sennoside, flavonol glycosides, triterpenoids and coumarin conjugated with gallic acids (E. Creencia, et al., KIMIKA (1996) 12: 1-10).
Chemical constituents isolated from T. chebula may vary considerably in type and/or concentration due to a number of factors, e.g., ecological variation, soil variation, and nutrient variation, as well as variations in the process of extraction.
Terminalia bellirica (Gaertn.) Roxb. (a.k.a. as Terminalia bellerica) (“TB”) is grown widely throughout India, Sri Lanka, and South East Asia. T. bellirica has been used for centuries in Ayurveda, and contains several constituents in common with T. chebula (Saraswathi, et al., Intl. J. Res. Pharm. Biomed. Sci. (2012) 3(1):97-99).
Xanthine oxidase (“XO”) is an enzyme that catalyzes the oxidation of hypoxanthine to xanthine and can further catalyze the oxidation of xanthine to uric acid. This enzyme plays an important role in the catabolism of purines in some species, including humans. However, sustained elevation of uric acid in blood can cause various diseases, including gout. In patients having gout, excess uric acid result in uric acid crystals which accumulate in cartilage, ligament and surrounding tissues causing severe inflammation and pain.
A xanthine oxidase inhibitor (XO inhibitor) is any substance that inhibits the enzymatic activity of XO, an enzyme involved in purine metabolism. In humans, inhibition of XO reduces the production of uric acid, and several medications that inhibit XO are indicated for treatment of hyperuricemia and related medical conditions including gout. XO inhibitors are also being investigated for management of reperfusion injury. Thus the therapeutic area relevant to XO inhibitors may include stroke, myocardial ischemia, hypertension, diabetes, reperfusion of liver, kidney and lungs, atherosclerosis, hypercholesteremia, inflammatory bowel disease (IBD), among others (Soni, et al., Intl. Pharm. Scientia (2011) 1(1):107-114).
The classes of XO inhibitors include purine analogues (such as allopurinol and oxypurinol), inositols (phytic acid and myo-inositol), and febuxostat (a phenylthiazole). WO 1992/009279 describes the inhibitory effect of thiazoles and phenyl derivatives against xanthine oxidase, and WO 2008/126898 reports that indole compounds exhibit an inhibitory effect against xanthine oxidase. Recently, WO 2010/093191 reported a series of indole-thiazole compounds having uric acid lowering properties and having potency similar to febuxostat. These products, however, have side effects, some of them serious, and it would be desirable to have non-toxic plant derived products, substantiated by proof of clinical efficacy, to treat hyperuricemia.
In view of the above, two Ayurvedic products, Terminalia chebula and Terminalia bellerica were studied in-vitro to determine their xanthine oxidase inhibitory activity and clinically in humans to determine their efficacy to lower Serum Uric acid levels.